Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Taru A Muranen; Dario Greco; Carl Blomqvist; Kristiina Aittomäki; Sofia Khan; Frans Hogervorst; Senno Verhoef; Paul D P Pharoah; Alison M Dunning; Mitul Shah; Robert Luben; Stig E Bojesen; Børge G Nordestgaard; Minouk Schoemaker; Anthony Swerdlow; Montserrat García-Closas; Jonine Figueroa; Thilo Dörk; Natalia V Bogdanova; Per Hall; Jingmei Li; Elza Khusnutdinova; Marina Bermisheva; Vessela Kristensen; Anne-Lise Borresen-Dale; Nbcs Investigators; Julian Peto; Isabel Dos Santos Silva; Fergus J Couch; Janet E Olson; Peter Hillemans; Tjoung-Won Park-Simon; Hiltrud Brauch; Ute Hamann; Barbara Burwinkel; Frederik Marme; Alfons Meindl; Rita K Schmutzler; Angela Cox; Simon S Cross; Elinor J Sawyer; Ian Tomlinson; Diether Lambrechts; Matthieu Moisse; Annika Lindblom; Sara Margolin; Antoinette Hollestelle; John W M Martens; Peter A Fasching; Matthias W Beckmann; Irene L Andrulis; Julia A Knight; kConFab/Aocs Investigators; Hoda Anton-Culver; Argyrios Ziogas; Graham G Giles; Roger L Milne; Hermann Brenner; Volker Arndt; Arto Mannermaa; Veli-Matti Kosma; Jenny Chang-Claude; Anja Rudolph; Peter Devilee; Caroline Seynaeve; John L Hopper; Melissa C Southey; Esther M John; Alice S Whittemore; Manjeet K Bolla; Qin Wang; Kyriaki Michailidou; Joe Dennis; Douglas F Easton; Marjanka K Schmidt; Heli Nevanlinna

doi:10.1038/gim.2016.147

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Taru A Muranen, Dario Greco, Carl Blomqvist, Kristiina Aittomäki, Sofia Khan, Frans Hogervorst, Senno Verhoef, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Stig E Bojesen, Børge G Nordestgaard, Minouk Schoemaker, Anthony Swerdlow, Montserrat García-Closas, Jonine Figueroa, Thilo Dörk, Natalia V Bogdanova, Per HallJingmei Li, Elza Khusnutdinova, Marina Bermisheva, Vessela Kristensen, Anne-Lise Borresen-Dale, Nbcs Investigators, Julian Peto, Isabel Dos Santos Silva, Fergus J Couch, Janet E Olson, Peter Hillemans, Tjoung-Won Park-Simon, Hiltrud Brauch, Ute Hamann, Barbara Burwinkel, Frederik Marme, Alfons Meindl, Rita K Schmutzler, Angela Cox, Simon S Cross, Elinor J Sawyer, Ian Tomlinson, Diether Lambrechts, Matthieu Moisse, Annika Lindblom, Sara Margolin, Antoinette Hollestelle, John W M Martens, Peter A Fasching, Matthias W Beckmann, Irene L Andrulis, Julia A Knight, kConFab/Aocs Investigators, Hoda Anton-Culver, Argyrios Ziogas, Graham G Giles, Roger L Milne, Hermann Brenner, Volker Arndt, Arto Mannermaa, Veli-Matti Kosma, Jenny Chang-Claude, Anja Rudolph, Peter Devilee, Caroline Seynaeve, John L Hopper, Melissa C Southey, Esther M John, Alice S Whittemore, Manjeet K Bolla, Qin Wang, Kyriaki Michailidou, Joe Dennis, Douglas F Easton, Marjanka K Schmidt, Heli Nevanlinna

Institut for Klinisk Medicin

36 Citationer (Scopus)

Abstract

Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.

Originalsprog	Engelsk
Tidsskrift	Genetics In Medicine
Vol/bind	19
Udgave nummer	5
Sider (fra-til)	599-603
ISSN	1098-3600
DOI	https://doi.org/10.1038/gim.2016.147
Status	Udgivet - 1 maj 2017

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1038/gim.2016.147

gim2016147.pdfForlagets udgivne version, 895 KB

Citationsformater

Muranen, T. A., Greco, D., Blomqvist, C., Aittomäki, K., Khan, S., Hogervorst, F., Verhoef, S., Pharoah, P. D. P., Dunning, A. M., Shah, M., Luben, R., Bojesen, S. E., Nordestgaard, B. G., Schoemaker, M., Swerdlow, A., García-Closas, M., Figueroa, J., Dörk, T., Bogdanova, N. V., ... Nevanlinna, H. (2017). Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics In Medicine, 19(5), 599-603. https://doi.org/10.1038/gim.2016.147

Muranen, TA, Greco, D, Blomqvist, C, Aittomäki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE , Nordestgaard, BG, Schoemaker, M, Swerdlow, A, García-Closas, M, Figueroa, J, Dörk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Investigators, N, Peto, J, Dos Santos Silva, I, Couch, FJ, Olson, JE, Hillemans, P, Park-Simon, T-W, Brauch, H, Hamann, U, Burwinkel, B, Marme, F, Meindl, A, Schmutzler, RK, Cox, A, Cross, SS, Sawyer, EJ, Tomlinson, I, Lambrechts, D, Moisse, M, Lindblom, A, Margolin, S, Hollestelle, A, Martens, JWM, Fasching, PA, Beckmann, MW, Andrulis, IL, Knight, JA, Investigators, KCA, Anton-Culver, H, Ziogas, A, Giles, GG, Milne, RL, Brenner, H, Arndt, V, Mannermaa, A, Kosma, V-M, Chang-Claude, J, Rudolph, A, Devilee, P, Seynaeve, C, Hopper, JL, Southey, MC, John, EM, Whittemore, AS, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Easton, DF, Schmidt, MK & Nevanlinna, H 2017, 'Genetic modifiers of CHEK2*1100delC-associated breast cancer risk', Genetics In Medicine, bind 19, nr. 5, s. 599-603. https://doi.org/10.1038/gim.2016.147

@article{a6f47a5348d242e59409f021b61b96cc,

title = "Genetic modifiers of CHEK2*1100delC-associated breast cancer risk",

abstract = "Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.",

author = "Muranen, {Taru A} and Dario Greco and Carl Blomqvist and Kristiina Aittom{\"a}ki and Sofia Khan and Frans Hogervorst and Senno Verhoef and Pharoah, {Paul D P} and Dunning, {Alison M} and Mitul Shah and Robert Luben and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and Minouk Schoemaker and Anthony Swerdlow and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Thilo D{\"o}rk and Bogdanova, {Natalia V} and Per Hall and Jingmei Li and Elza Khusnutdinova and Marina Bermisheva and Vessela Kristensen and Anne-Lise Borresen-Dale and Nbcs Investigators and Julian Peto and {Dos Santos Silva}, Isabel and Couch, {Fergus J} and Olson, {Janet E} and Peter Hillemans and Tjoung-Won Park-Simon and Hiltrud Brauch and Ute Hamann and Barbara Burwinkel and Frederik Marme and Alfons Meindl and Schmutzler, {Rita K} and Angela Cox and Cross, {Simon S} and Sawyer, {Elinor J} and Ian Tomlinson and Diether Lambrechts and Matthieu Moisse and Annika Lindblom and Sara Margolin and Antoinette Hollestelle and Martens, {John W M} and Fasching, {Peter A} and Beckmann, {Matthias W} and Andrulis, {Irene L} and Knight, {Julia A} and kConFab/Aocs Investigators and Hoda Anton-Culver and Argyrios Ziogas and Giles, {Graham G} and Milne, {Roger L} and Hermann Brenner and Volker Arndt and Arto Mannermaa and Veli-Matti Kosma and Jenny Chang-Claude and Anja Rudolph and Peter Devilee and Caroline Seynaeve and Hopper, {John L} and Southey, {Melissa C} and John, {Esther M} and Whittemore, {Alice S} and Bolla, {Manjeet K} and Qin Wang and Kyriaki Michailidou and Joe Dennis and Easton, {Douglas F} and Schmidt, {Marjanka K} and Heli Nevanlinna",

year = "2017",

month = may,

day = "1",

doi = "10.1038/gim.2016.147",

language = "English",

volume = "19",

pages = "599--603",

journal = "Genetics In Medicine",

issn = "1098-3600",

publisher = "nature publishing group",

number = "5",

}

TY - JOUR

T1 - Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

AU - Muranen, Taru A

AU - Greco, Dario

AU - Blomqvist, Carl

AU - Aittomäki, Kristiina

AU - Khan, Sofia

AU - Hogervorst, Frans

AU - Verhoef, Senno

AU - Pharoah, Paul D P

AU - Dunning, Alison M

AU - Shah, Mitul

AU - Luben, Robert

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Schoemaker, Minouk

AU - Swerdlow, Anthony

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Dörk, Thilo

AU - Bogdanova, Natalia V

AU - Hall, Per

AU - Li, Jingmei

AU - Khusnutdinova, Elza

AU - Bermisheva, Marina

AU - Kristensen, Vessela

AU - Borresen-Dale, Anne-Lise

AU - Investigators, Nbcs

AU - Peto, Julian

AU - Dos Santos Silva, Isabel

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Hillemans, Peter

AU - Park-Simon, Tjoung-Won

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Cox, Angela

AU - Cross, Simon S

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Lambrechts, Diether

AU - Moisse, Matthieu

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Hollestelle, Antoinette

AU - Martens, John W M

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Andrulis, Irene L

AU - Knight, Julia A

AU - Investigators, kConFab/Aocs

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Giles, Graham G

AU - Milne, Roger L

AU - Brenner, Hermann

AU - Arndt, Volker

AU - Mannermaa, Arto

AU - Kosma, Veli-Matti

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Devilee, Peter

AU - Seynaeve, Caroline

AU - Hopper, John L

AU - Southey, Melissa C

AU - John, Esther M

AU - Whittemore, Alice S

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Michailidou, Kyriaki

AU - Dennis, Joe

AU - Easton, Douglas F

AU - Schmidt, Marjanka K

AU - Nevanlinna, Heli

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.

AB - Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.

U2 - 10.1038/gim.2016.147

DO - 10.1038/gim.2016.147

M3 - Letter

C2 - 27711073

SN - 1098-3600

VL - 19

SP - 599

EP - 603

JO - Genetics In Medicine

JF - Genetics In Medicine

IS - 5

ER -

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater